Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.
Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.
复制标题
DOI：
10.1161/circulationaha.116.023711
复制
发表时间：
2017-09-05
期刊：
影响因子：
37.8
通讯作者：
Rao AK
中科院分区：
文献类型：
--
作者：
Mao G;Songdej N;Voora D;Goldfinger LE;Del Carpio-Cano FE;Myers RA;Rao AK
磷脂酰胆碱转移蛋白（PCTP）调控磷脂酰胆碱（PC）的膜间转移。与白人受试者相比，黑人受试者中较高的血小板PCTP表达与蛋白酶激活受体4 （PAR4）凝血酶受体激活后血小板反应增加有关。关于血小板PCTP的调控知之甚少。RUNX1是一种主要的造血转录因子，其单倍体缺陷与血小板减少症和活化后血小板反应受损有关。我们描述的RUNX1功能缺失突变患者的血小板表达谱显示，与健康对照相比，PCTP基因下调了10倍。我们假设PCTP受RUNX1调控，并且PCTP的表达与心血管事件相关。我们利用dna -蛋白结合研究和人红细胞白血病（HEL）细胞研究了RUNX1与PCTP启动子的结合，并利用荧光素酶报告基因研究了启动子的活性。我们在两个独立的心血管疾病患者队列（共587例患者）中评估了外周血RNA和PCTP中RUNX1和PCTP与死亡或心肌梗死（MI）之间的关系。患者血小板PCTP蛋白降低约50%。dna -蛋白结合研究表明，RUNX1与PCTP启动子约1kb的一致位点结合。在HEL细胞中，PCTP表达随RUNX1过表达而升高，随RUNX1敲低而降低，说明PCTP受RUNX1调控。两组患者的研究表明，血液中RUNX1表达与PCTP基因表达相关；PCTP在黑人中的表达高于白人，并且在调整年龄、性别和种族后与未来死亡/心肌梗死相关（优势比2.05,95% CI [1.6-2.7]， p值< 0.0001）。已知RUNX1的表达在两个交替启动子上启动，一个远端P1启动子和一个近端P2启动子。在患者队列中，RUNX1亚型对PCTP表达的影响存在差异，血液中P1启动子表达的RUNX1与PCTP表达呈负相关。PCTP是RUNX1的直接转录靶点。PCTP表达与心血管疾病患者死亡/心肌梗死相关RUNX1调控PCTP可能在血小板介导的心血管事件的发病机制中发挥作用。
Phosphatidylcholine Transfer Protein (PCTP) regulates the intermembrane transfer of phosphatidylcholine (PC). Higher platelet PCTP expression is associated with increased platelet responses upon activation of protease-activated receptor 4 (PAR4) thrombin receptors noted in black subjects as compared to white subjects. Little is known regarding regulation of platelet PCTP. Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses upon activation. Platelet expression profiling of a patient described by us with a RUNX1 loss-of-function mutation revealed a 10-fold downregulation of PCTP gene compared with healthy controls. We pursued the hypothesis that PCTP is regulated by RUNX1 and that PCTP expression is correlated with cardiovascular events. We studied RUNX1 binding to PCTP promoter using DNA-protein binding studies and human erythroleukemia (HEL) cells, and promoter activity using luciferase reporter studies. We assessed the relationship between RUNX1 and PCTP in peripheral blood RNA and PCTP and death or myocardial infarction (MI) in two separate patient cohorts (587 total patients) with cardiovascular disease. Platelet PCTP protein in the patient was reduced by ~50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ~1 kB of PCTP promoter. PCTP expression was increased with RUNX1 overexpression and reduced with RUNX1 knockdown in HEL cells, indicating that PCTP is regulated by RUNX1. Studies in two cohorts of patients showed that RUNX1 expression in blood correlated with PCTP gene expression; PCTP expression was higher in black compared to white subjects, and associated with future death/myocardial infarction after adjusting for age, sex, and race (odds ratio 2.05, 95% CI [1.6–2.7], P-value < 0.0001). RUNX1 expression is known to initiate at two alternate promoters, a distal P1 and a proximal P2 promoter. In patient cohorts there were differential effects of RUNX1 isoforms on PCTP expression with a negative correlation in blood between RUNX1 expressed from the P1 promoter and PCTP expression. PCTP is a direct transcriptional target of RUNX1. PCTP expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events.